tbuckley/cabot-search huggingface dataset:
Membrane‐Active Metallopolymers: Repurposing and Rehabilitating Antibiotics to Gram‐Negative Superbugs
Authors: JiHyeon Hwang, Swagatam Barman, Ruixuan Gao, Xiaoming Yang, Andrea O'Malley, Prakash Nagarkatti, Mitzi Nagarkatti, Maksymilian Chruszcz, Chuanbing Tang
Journal: Advanced Healthcare Materials (2023)

Among multiple approaches to combating antimicrobial resistance, a combination therapy of existing antibiotics with bacterial membrane-perturbing agents is promising. A viable platform of metallopolymers as adjuvants in combination with traditional antibiotics is reported in this work to combat both planktonic and stationary cells of Gram-negative superbugs and their biofilms. Antibacterial efficacy, toxicity, antibiofilm activity, bacterial resistance propensity, and mechanisms of action of metallopolymer-antibiotic combinations are investigated. These metallopolymers exhibit 4-16-fold potentiation of antibiotics against Gram-negative bacteria with negligible toxicity toward mammalian cells. More importantly, the lead combinations (polymer-ceftazidime and polymer-rifampicin) eradicate preformed biofilms of MDR E. coli and P. aeruginosa, respectively. Further, β-lactamase inhibition, outer membrane permeabilization, and membrane depolarization demonstrate synergy of these adjuvants with different antibiotics. Moreover, the membrane-active metallopolymers enable the antibiotics to circumvent bacterial resistance development. Altogether, the results indicate that such non-antibiotic adjuvants bear the promise to revitalize the efficacy of existing antibiotics to tackle Gram-negative bacterial infections.
The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer
Authors: Austin K. Mattox, Christopher Douville, Yuxuan Wang, Maria Popoli, Janine Ptak, Natalie Silliman, Lisa Dobbyn, Joy Schaefer, Steve Lu, Alexander H. Pearlman, Joshua D. Cohen, Jeanne Tie, Peter Gibbs, Kamel Lahouel, Chetan Bettegowda, Ralph H. Hruban, Cristian Tomasetti, Peiyong Jiang, K.C. Allen Chan, Yuk Ming Dennis Lo, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein
Journal: Cancer Discovery (2023)

Cell-free DNA (cfDNA) concentrations from patients with cancer are often elevated compared with those of healthy controls, but the sources of this extra cfDNA have never been determined. To address this issue, we assessed cfDNA methylation patterns in 178 patients with cancers of the colon, pancreas, lung, or ovary and 64 patients without cancer. Eighty-three of these individuals had cfDNA concentrations much greater than those generally observed in healthy subjects. The major contributor of cfDNA in all samples was leukocytes, accounting for ∼76% of cfDNA, with neutrophils predominating. This was true regardless of whether the samples were derived from patients with cancer or the total plasma cfDNA concentration. High levels of cfDNA observed in patients with cancer did not come from either neoplastic cells or surrounding normal epithelial cells from the tumor's tissue of origin. These data suggest that cancers may have a systemic effect on cell turnover or DNA clearance. The origin of excess cfDNA in patients with cancer is unknown. Using cfDNA methylation patterns, we determined that neither the tumor nor the surrounding normal tissue contributes this excess cfDNA-rather it comes from leukocytes. This finding suggests that cancers have a systemic impact on cell turnover or DNA clearance. See related commentary by Thierry and Pisareva, p. 2122. This article is featured in Selected Articles from This Issue, p. 2109.
CCND2 Modified mRNA Activates Cell Cycle of Cardiomyocytes in Hearts With Myocardial Infarction in Mice and Pigs
Authors: Jiacheng Sun, Lu Wang, Rachel C. Matthews, Gregory P. Walcott, Yu-An Lu, Yuhua Wei, Yang Zhou, Lior Zangi, Jianyi Zhang
Journal: Circulation Research (2023)

Experiments in mammalian models of cardiac injury suggest that the cardiomyocyte-specific overexpression of CCND2 (cyclin D2, in humans) improves recovery from myocardial infarction (MI). The primary objective of this investigation was to demonstrate that our specific modified mRNA translation system (SMRTs) can induce CCND2 expression in cardiomyocytes and replicate the benefits observed in other studies of cardiomyocyte-specific CCND2 overexpression for myocardial repair.
Spatiotemporally controlled Pseudomonas exotoxin transgene system combined with multifunctional nanoparticles for breast cancer antimetastatic therapy
Authors: Yi Cheng, Jiafeng Zou, Muye He, Xinyu Hou, Hongtao Wang, Jiajun Xu, Zeting Yuan, Minbo Lan, Yi Yang, Xianjun Chen, Feng Gao
Journal: Journal of Controlled Release (2024)
Perceptions of Safety of Daily Cannabis vs Tobacco Smoking and Secondhand Smoke Exposure, 2017-2021
Authors: Julia Chambers, Salomeh Keyhani, Pamela M. Ling, Katherine J. Hoggatt, Deborah Hasin, Nhung Nguyen, Anne Woods, Annie Ryder, Beth E. Cohen
Journal: JAMA Network Open (2023)

While rates of cigarette use are declining, more US adults are using cannabis. Perceptions of safety are important drivers of substance use and public policy; however, little is known about the comparative views of US adults on tobacco and cannabis safety.To compare public perceptions of safety of cannabis vs tobacco smoke and evaluate how perceptions may be changing over time.This longitudinal survey study was conducted using a web-based survey administered in 2017, 2020, and 2021. US adults participating in Ipsos KnowledgePanel, a nationally representative, population-based survey panel, were included. Data were analyzed from March 2021 through June 2023.Two questions directly compared the perception of safety of cannabis vs tobacco in terms of daily smoking and secondhand smoke exposure. Additional questions assessed perceptions of safety of secondhand tobacco smoke for adults, children, and pregnant women, with an analogous set of questions for secondhand cannabis smoke.A total of 5035 participants (mean [SD] age, 53.4 [16.2] years; 2551 males [50.7%]) completed all 3 surveys and provided responses for tobacco and cannabis risk questions. More than one-third of participants felt that daily smoking of cannabis was safer than tobacco, and their views increasingly favored safety of cannabis vs tobacco over time (1742 participants [36.7%] in 2017 vs 2107 participants [44.3%] in 2021; P < .001). The pattern was similar for secondhand cannabis smoke, with 1668 participants (35.1%) responding that cannabis was safer than tobacco in 2017 vs 1908 participants (40.2%) in 2021 (P < .001). Participants who were younger (adjusted odds ratio [aOR] for ages 18-29 years vs ≥60 years, 1.4 [95% CI, 1.1-1.8]; P = .01) or not married (aOR, 1.2 [95% CI, 1.0-1.4]; P = .01) were more likely to move toward safer views of cannabis use over time, while those who were retired (aOR vs working, 0.8 [95% CI, 0.7-0.9]; P = .01) were less likely to move toward a safer view of cannabis. Participants were also more likely to rate secondhand smoke exposure to cannabis vs tobacco as completely or somewhat safe in adults (629 participants [12.6%] vs. 119 participants [2.4%]; P < .001), children (238 participants [4.8%] vs. 90 participants [1.8%]; P < .001), and pregnant women (264 participants [5.3%] vs. 69 participants [1.4%]; P < .001).This study found that US adults increasingly perceived daily smoking and secondhand exposure to cannabis smoke as safer than tobacco smoke from 2017 to 2021. Given that these views do not reflect the existing science on cannabis and tobacco smoke, the findings may have important implications for public health and policy as the legalization and use of cannabis increase.
Survival benefit of living-donor liver transplantation in patients with a model for end-stage liver disease over 30 in a region with severe organ shortage: a retrospective cohort study
Authors: Seung Hyuk Yim, Deok-Gie Kim, Minyu Kang, Hwa-Hee Koh, Mun Chae Choi, Eun-Ki Min, Jae Geun Lee, Myoung Soo Kim, Dong Jin Joo
Journal: International Journal of Surgery (2023)

The benefits of living-donor liver transplantation (LDLT) in patients with a high Model for End-stage Liver Disease (MELD) score (who have high waitlist mortality) are unclear. Regional availability of deceased-donor organs must be considered when evaluating LDLT benefits. The authors aimed to compare the survival benefit of intended-LDLT to awaiting deceased-donor liver transplantation (DDLT) in patients with a MELD score greater than or equal to 30 in a region with severe organ shortage.This retrospective review included 649 patients with a MELD score greater than or equal to 30 placed on the liver transplantation waitlist. They were divided into intended-LDLT ( n =205) or waiting-DDLT ( n =444) groups based on living-donor eligibility and compared for patient survival from the time of waitlisting. Post-transplantation outcomes of transplant recipients and living donors were analyzed.Intended-LDLT patients had higher 1-year survival than waiting-DDLT patients (53.7 vs. 28.8%, P <0.001). LDLT was independently associated with lower mortality [hazard ratio (HR), 0.62; 95% CI, 0.48-0.79; P <0.001]. During follow-up, 25 patients were de-listed, 120 underwent LDLT, 170 underwent DDLT, and 334 remained on the waitlist. Among patients undergoing transplantation, the risk of post-transplantation mortality was similar for LDLT and DDLT after adjusting for pretransplantation MELD score (HR, 1.86; 95% CI, 0.73-4.75; P =0.193), despite increased surgical complications after LDLT (33.1 vs. 19.4%, P =0.013). There was no mortality among living-donors, but 4.2% experienced complications of grade 3 or higher.Compared to awaiting DDLT, LDLT offers survival benefits for patients with a MELD score greater than or equal to 30, while maintaining acceptable donor outcomes. LDLT is a feasible treatment for patients with a MELD score greater than or equal to 30 in regions with severe organ shortages.
Association of Caregiver Depression Risk With Patient Outcomes in Parkinson Disease
Authors: Rudmila Rashid, Whitley W. Aamodt, Sarah Horn, Nabila Dahodwala
Journal: JAMA Network Open (2023)

Caregivers are integral to Parkinson disease (PD) care, but little information exists regarding how caregivers impact patient outcomes.To assess the association between caregivers reporting depression symptoms and patient quality of life (QOL), emergency department (ED) visits, and hospitalizations.This retrospective cohort study was conducted at 15 Parkinson's Foundation Centers of Excellence within the US. The Parkinson's Foundation Parkinson Outcomes Project registry was used to collect baseline data from January 1, 2016, to December 31, 2018, with subsequent annual study visits through July 31, 2020. Data were analyzed from August 5, 2020, to June 9, 2023. A convenience sample of 454 patients with PD and their caregivers was recruited during routine clinical visits with movement disorder specialists. Patients with a physician diagnosis of idiopathic PD who lived at home and had 1 or more follow-up study visits were included.Caregiver depression symptoms using the Center for Epidemiologic Studies Depression Scale.Patient health-related QOL (measured by the 39-item Parkinson Disease Questionnaire), number of annual ED visits, and number of annual hospitalizations were measured. The independent association between caregivers reporting depression symptoms and patient outcomes was assessed using linear mixed-effects and Poisson regression models. The a priori hypotheses were that a greater number of depression symptoms reported via the Center for Epidemiologic Studies Depression Scale would be associated with worse patient QOL and a greater number of ED visits and hospitalizations.Among 454 patient-caregiver dyads (patients: mean [SD] age, 67.3 [8.4] years; 320 men [70.5%]; caregivers: mean [SD] age, 65.9 [8.7] years; 326 women [71.8%]), the mean (SD) follow-up was 2.0 (1.4) study visits. Greater depression symptoms among caregivers were associated with worse patient QOL as measured by the Parkinson Disease Questionnaire (mean [SD] score, 33.78 [17.71], on a scale of 0-100, with higher scores indicating worse QOL, among patients with caregivers who had depression symptoms vs 24.50 [14.19] among patients with caregivers who did not have depression symptoms; β = 0.43; 95% CI, 0.28-0.58; P < .001) and more annual ED visits (β = 0.02; 95% CI, 0 to 0.04; P = .03) but not more hospitalizations (β = 0.02; 95% CI, -0.01 to 0.03; P = .10).In this cohort study, patients with PD who had caregivers at higher risk of depression were more likely to have worse QOL and higher ED use than patients who had caregivers not at higher risk of depression. Additional caregiving resources and interventions to reduce caregiver depression symptoms could potentially improve patient outcomes.
Errors in the Byline
Journal: JAMA Network Open (2023)

Shima Espahbodi, PhD; Eef Hogervorst, PhD; Tara-Mei Povall Macnab, BSc; Ahmed Thanoon, MSc; Gwen Sacha Fernandes, PhD; Bonnie Millar, PhD; Ashley Duncan, MSc; Maria Goodwin, MSc; Mark Batt, MBBChir; Colin W. Fuller, PhD; Gordon Fuller, PhD; Eamonn Ferguson, PhD; Tobias Bast, PhD; Michael Doherty, MD; Weiya Zhang, PhD
Error in Results
Journal: JAMA Network Open (2023)

Error in ResultsIn the Original Investigation titled "Smart Thermometer-Based Participatory Surveillance to Discern the Role of Children in Household Viral Transmission During the COVID-19 Pandemic," 1 published June 1, 2023, total individuals in the surveillance network were used when the households with adults and children were more relevant to study results.In the Results, the total number of participants has been changed from 516 159 to 516 084, and total children from 265 268 to 265 193; percentages of younger and older children that were index cases of households have been updated with 147 305 younger and 117 888 older children as the denominators, respectively.Additionally, language in the Key Points, Discussion, and Conclusion has been updated to clarify the study population.This article has been corrected.
The Ghent Psychotherapy Study: A Pragmatic, Stratified, Randomized Parallel Trial into the Differential Efficacy of Psychodynamic and Cognitive-Behavioral Interventions in Dependent and Self-Critical Depressive Patients
Authors: Reitske Meganck, Mattias Desmet, Kimberly Van Nieuwenhove, Melissa De Smet, Vicky Hennissen, Femke Truijens, Rosa De Geest, Goedele Hermans, Claudi Bockting, Ufuoma Angelica Norman, Tom Loeys, Ruth Inslegers, Tim Van den Abeele, Chris Baeken, Stijn Vanheule
Journal: Psychotherapy and Psychosomatics (2023)

Different types of psychotherapy are effective for treating major depressive disorder across groups yet show large within-group differences. Patient personality style is considered a potentially useful variable for treatment matching.This study is the first experimental test of the interaction between therapeutic approach and patients' dependent versus self-critical personality styles.A pragmatic stratified parallel trial was carried out with 100 adult patients diagnosed with DSM-IV-TR major depressive disorder. They were randomly assigned to short-term (16-20 sessions) cognitive behavioral therapy (CBT) or short-term psychodynamic psychotherapy (STPP). Patients were assessed at baseline, during therapy, post-therapy, and at 3- and 6-month follow-up. Primary outcome is depression severity measured by the Hamilton Rating Scale for Depression posttreatment. Primary analysis was by intention to treat. This trial is registered with the ISRCTN registry (<ext-link ext-link-type="uri" xlink:href="http://www.isrctn.com" xmlns:xlink="http://www.w3.org/1999/xlink">www.isrctn.com</ext-link>), number ISRCTN17130982.The intention-to-treat sample consisted of 100 participants; 40 with self-critical and 60 with dependent personality styles were randomized to either CBT (n = 50) or STPP (n = 50). We observed no interaction effect (-0.34 [-6.14, 5.46]) between therapy and personality style and found no evidence for a difference in effectiveness between the treatments in general in terms of symptom reduction and maintained benefits at 6-month follow-up.We found no evidence that dependent versus self-critical personality styles moderate the relation between treatment and outcome in depression. Research using individual patient data could gain further insight into why specific therapeutic approaches work better for specific patients.
Strong Purifying Selection in Haploid Tissue–Specific Genes of Scots Pine Supports the Masking Theory
Authors: Sandra Cervantes, Robert Kesälahti, Timo A Kumpula, Tiina M Mattila, Heikki Helanterä, Tanja Pyhäjärvi
Journal: Molecular Biology and Evolution (2023)

The masking theory states that genes expressed in a haploid stage will be under more efficient selection. In contrast, selection will be less efficient in genes expressed in a diploid stage, where the fitness effects of recessive deleterious or beneficial mutations can be hidden from selection in heterozygous form. This difference can influence several evolutionary processes such as the maintenance of genetic variation, adaptation rate, and genetic load. Masking theory expectations have been confirmed in single-cell haploid and diploid organisms. However, in multicellular organisms, such as plants, the effects of haploid selection are not clear-cut. In plants, the great majority of studies indicating haploid selection have been carried out using male haploid tissues in angiosperms. Hence, evidence in these systems is confounded with the effects of sexual selection and intraspecific competition. Evidence from other plant groups is scarce, and results show no support for the masking theory. Here, we have used a gymnosperm Scots pine megagametophyte, a maternally derived seed haploid tissue, and four diploid tissues to test the strength of purifying selection on a set of genes with tissue-specific expression. By using targeted resequencing data of those genes, we obtained estimates of genetic diversity, the site frequency spectrum of 0-fold and 4-fold sites, and inferred the distribution of fitness effects of new mutations in haploid and diploid tissue-specific genes. Our results show that purifying selection is stronger for tissue-specific genes expressed in the haploid megagametophyte tissue and that this signal of strong selection is not an artifact driven by high expression levels.
Headpulse Biometric Measures Following Concussion in Young Adult Athletes
Authors: Cathra Halabi, Lynda Norton, Kevin Norton, Wade S. Smith
Journal: JAMA Network Open (2023)

Concussions are common in sports. Return-to-play protocols can be enhanced by objective biometrics.To characterize temporal changes of headpulse, a digital biometric, in athletes with sports-related concussion; to explore the association of unstructured physical activity with headpulse changes.This cohort study included headpulse measurements from players in the highest level of amateur Australian Rules Football in South Australia. Analysis included feasibility and validation phases, with the feasibility cohort recruited between August 5, 2021, and September 10, 2021, and the validation cohort recruited between May 5, 2022, and September 3, 2022. Data were analyzed October 2022 through January 2023.Cranial accelerometry detected micromovements of the head following cardiac contraction (what we have described as "headpulse"). Headpulse was serially recorded for 1 month in concussed individuals.Headpulse waveforms underwent frequency transformation analysis per prespecified algorithm. Result Z scores were calculated. Headpulse Z scores exceeding 2 (2 SDs from control means) met an abnormality threshold. Headpulse sensitivity, timing, and duration of change were determined.A total of 59 control and 43 concussed individuals (44 total concussions; 1 control also concussed, 1 concussed individual injured twice) provided headpulse measurements. The feasibility cohort (all male) included 17 control (median [IQR] age, 23 [19-28] years) and 15 concussed individuals (median [IQR] age, 21 [19-23] years). The validation cohort included 25 female (median [IQR] age, 21 [20-22] years) and 17 male (median [IQR] age, 26 [23-29] years) control individuals, and 8 female (median [IQR] age, 28 [20-31] years) and 20 male (median [IQR] age, 21 [19-23] years) concussed individuals. Headpulse reached abnormality threshold in 26 of 32 concussed individuals (81%; 9% on day 0, 50% by day 2, 90% by day 14). Headpulse alterations lasted 14 days longer than symptoms and were exacerbated by return-to-play or unsupervised physical activity.In this study of 101 amateur Australian Rules Football athletes, the digital headpulse biometric was evaluated in 44 sports-related concussions. Compared with controls, new headpulse changes occurred after concussion; this objective metric may complement return-to-play protocols.
Immune Marker Spatial Distribution and Clinical Outcome after PD-1 Blockade in Mismatch Repair–deficient, Advanced Colorectal Carcinomas
Authors: Bahar Saberzadeh-Ardestani, Rondell P. Graham, Sara McMahon, Eze Ahanonu, Qian Shi, Crystal Williams, Antony Hubbard, Wenjun Zhang, Andrea Muranyi, Dongyao Yan, Zhaohui Jin, Kandavel Shanmugam, Frank A. Sinicrope
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) interaction has led to durable responses in fewer than half of patients with mismatch repair–deficient (MMR-d) advanced colorectal cancers. Immune contexture, including spatial distribution of immune cells in the tumor microenvironment (TME), may predict immunotherapy outcome. Experimental Design: Immune contexture and spatial distribution, including cell-to-cell distance measurements, were analyzed by multiplex immunofluorescence (mIF) in primary colorectal cancers with d-MMR (N = 33) from patients treated with anti–PD-1 antibodies. By digital image analysis, density, ratio, intensity, and spatial distribution of PD-L1, PD-1, CD8, CD3, CD68, LAG3, TGFβR2, MHC-I, CD14, B2M, and pan-cytokeratin were computed. Feature selection was performed by regularized Cox regression with LASSO, and a proportional hazards model was fitted to predict progression-free survival (PFS). Results: For predicting survival among patients with MMR-d advanced colorectal cancer receiving PD-1 blockade, cell-to-cell distance measurements, but not cell densities or ratios, achieved statistical significance univariately. By multivariable feature selection, only mean number of PD-1+ cells within 10 μm of a PD-L1+ cell was significantly predictive of PFS. Dichotomization of this variable revealed that those with high versus low values had significantly prolonged PFS [median not reached (&amp;gt;83 months) vs. 8.5 months (95% confidence interval (95% CI), 4.7–NR)] with a median PFS of 28.4 months for all patients [adjusted HR (HRadj) = 0.14; 95% CI, 0.04–0.56; P = 0.005]. Expression of PD-1 was observed on CD8+ T cells; PD-L1 on CD3+ and CD8+ T lymphocytes, macrophages (CD68+), and tumor cells. Conclusions: In d-MMR colorectal cancers, PD-1+ to PD-L1+ receptor to ligand proximity is a potential predictive biomarker for the effectiveness of PD-1 blockade.